Increasingly there is a need for effective treatments for nervous system disorders and neurological deficiencies. Many of these diseases correlate with increasing age, due mainly to degenerative changes in the nervous systems. Although in early stages of some diseases certain systems are rather specifically affected (e. g. cholinergic systems in Alzheimer's Disease and Myasthenia Gravis, the dopaminergic system in Parkinson's Disease, etc.), multiple neurotransmitter system deficiencies (acetylcholine, dopanine, norepinephrine, serotonin) are generally found at later stages of disease such as senile dementia, multi-infarct dementia, Huntington's Disease, mental retardation, etc. This explains the generally observed multiple symptomatology that includes cognitive, neurological, and effective/psychotic components (see Gottfries, Psychopharmacol., (1985) 86: 245). Deficits in the synthesis and release of acetylcholine in the brain are generally thought to be related to cognitive impairment (see Francis, et al., N. Engl. J. Med., (1985) 7: 313) whereas neurological deficits (e. g., Parkinsonian symptoms) and mood/mental changes may be related to impairment of dopaminergic and serotonergic systems, respectively. Other neurological deficits (e. g. Myastheiiia Gravis) are related to cholinergic deficiencies in the peripheral nervous system.
Treatment strategies employed previously encompass vasoactive drugs like vincamine and pentoxifylline; metabolic enhancers like ergoloid mesylates, piracetam, and naftidrofuryl; neurotransmitter precursors like 1-DOPA, choline, and 5-hydroxytryptamine; transmitter metabolizing enzyme inhibitors such as physostigmine; and neuropeptides like adrenocorticotropic hormone and vasopressin-related peptides. Except for L-DOPA treatment for Parkinson's Disease and cholinesterase inhibitor treatment for Myasthenia Gravis, these treatment strategies have generally failed to enhance the residual function of the affected systems by enhancing the stimulus-induced release of neurotransmitters. Theoretically, such an enhancement would improve the signal-to noise ratio during chemical transmission of information, thereby reducing deficits in processes related to cognition, neurological function, and mood regulation.
DeNoble, et al., Pharmacol. Biochem. Behavior, (1990) 36: 957; Cook, et al., Pharmacol. Biochem. Behavior, (1990) 19: 30:L; Nickolson, et al., Pharmacol. Biochem. Behavior, (1990) 19: 285; and U.S. Pat. No. 4,760,083 (1988), all have shown by in vitro testing that the compound 3,3-bis-(4-pyridinylmethyl)-1-phenylindolin-2-one is useful in the treatment of cognition dysfunction.
U.S. Pat. No. 5,173,489 issued Dec. 22, 1992 discloses .alpha.,.alpha.'-disubstituted aromatic or heteroaromatic compounds of the formula: ##STR2## or a salt thereof:
wherein X and Y are taken together to form a saturated ring or unsaturated carbocyclic or heterocyclic first ring and the shown carbon in said ring is .alpha. to at least one additional aromatic ring or heteroaromatic ring fused to the first ring; one of Het.sup.1 or Het.sup.2 is 2, 3, or 4-pyridinyl; or 2,4 or 5-pyrimidinyl, and the other is selected from
(a) 2, 3, or 4-pyridinyl PA1 (b) 2, 4, or 5-pyrimidinyl PA1 (c) 2-pyrazinyl PA1 (d) 3 or 4-pyridazinyl PA1 (e) 3 or 4-pyrazolyl PA1 (f) 2 or 3 tetrahydrofuranyl, and PA1 (g) 3-thienyl PA1 P is H, phenyl, C.sub.1 -C.sub.4 alkyl or benzyl PA1 R.sup.2 and R.sup.3 are independently H, F, Cl, Br, I, CF.sub.3, OH, R.sup.4, PA1 R.sup.2a is H, C.sub.1 -C.sub.4 alkyl or phenyl; PA1 m is 0, 1, or 2; PA1 R.sup.4 and R.sup.4a are independently alkyl of 1 to 4 carbons; PA1 Each of Het-1 and Het-2 is independently a heterocycle selected from the group consisting of: ##STR10## Each X is independently H, F, Cl, Br, I, CF.sub.3, OR.sup.4, NR.sup.6 R.sup.6a, NO.sub.2, or CN PA1 R is selected from the group consisting of: PA1 W is H, F, Cl, Br, --CN, CO.sub.2 R.sup.5, R.sup.4, OR.sup.4, S(O).sub.m --R.sup.4 ; PA1 Y is --OR.sup.6, NHR.sup.6, NR.sup.6 R.sup.6a , NHCOR.sup.6, NHCO.sub.2 R.sup.6, CO.sub.2 R.sup.6, --CN, PA1 n is 0 to 5 thereof. PA1 R.sup.5, R.sup.6 and R.sup.6a are independently H or alkyl of 1 to 6 carbons. PA1 A is an aromatic or heteroaromatic ring selected from the group consisting of: ##STR12## PA1 A is an aromatic or heteroaromatic ring selected from the group consisting of: ##STR13## B is an aromatic or heteroaromatic ring selected from the group consisting of: ##STR14## PA1 A is a six member aromatic or heteroaromatic ring selected from the group consisting of: ##STR15## B is an aromatic or heteroaromatic ring selected from the group consisting of: ##STR16## R.sup.2 is H, I, R.sup.4, --C.tbd.CH, --OR.sup.4, --NR.sup.6 R.sup.6a , --CO.sub.2 R.sup.4, or --CH.sub.2).sub.n NR.sup.6 COR.sup.4 ; PA1 R.sup.3 is H; PA1 Het-1 and Het-2 are independently ##STR17## X is H, F, Cl, Br, or OR.sup.4 ; R is selected from the group consisting of:
which are useful as cognition enhancers. The above references claim the necessity of two heteroaryl pendant groups for activity.
European Patent Application, WO93/14085, published Jul. 22, 1993 discloses compounds of the formula: ##STR3## where Q is ##STR4## which are useful as neurotransmitter release enhacers.
European Patent Application, WO93/14092, published Jul. 22, 1993, discloses compounds of the formula: ##STR5## where Q is ##STR6## which are useful as neurotransmitter release enhancers.
None of the above references teach or suggest the compounds of the present invention having fused polycyclic systems of the 6-5-5 variety where A is a six-membered aromatic system; B is a five-membered heterocyclic system and C is a five-membered ring between ring systems A and B. In addition, it has been further demonstrated that certain compounds of the present invention, particularly those bearing a 2-fluoropyridinylmethyl group as a substituent on the polycyclic ring system, have the ability to produce a measurable increase in the level of acetylcholine in the brain. This demonstrated ability to produce increases in acetylcholine levels meaurable directly in the brain constitutes a clear and unexpected advantage over compounds previously described in the art.